System, method and computer-accessible medium for in-vivo tissue ablation and/or damage

ABSTRACT

Systems, methods and computer-accessible mediums can be provided that can establish particular parameters for electric pulses based on a characteristic(s) of the tissue(s), and control an application of the electric pulses to tissue(s) for a plurality of automatically controlled and separated time periods to ablate the tissue(s) through mediation of membrane potential and through inducing the cells through a plurality of charge-discharge cycles such that an electroporation of a majority of the tissue(s) is prevented or reduced.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. National phase patentapplication Ser. No. 14/910,600, filed on Feb. 5, 2016, issuing as U.S.patent Ser. No. 10/709,491, on Jul. 14, 2020, which relates to andclaims the benefit and priority from International Patent ApplicationNo. PCT/US2014/049880 filed Aug. 6, 2014, which claims the benefit andpriority from U.S. Provisional Patent Application No. 61/862,580 filedon Aug. 6, 2013, the entire disclosures of which are incorporated hereinby reference.

FIELD OF THE DISCLOSURE

The present disclosure relates generally to exemplary system, method andcomputer-accessible medium for in-vivo tissue ablation, and morespecifically, to exemplary embodiments of the exemplary system methodand computer-accessible medium that can damage or kill tissue and/or oneor more cells using bioelectric pulses and/or cellular processes throughin-vivo tissue ablation.

BACKGROUND INFORMATION

Cells can have a transmembrane voltage that can be used to facilitateelectro-chemical transport of molecules and ions across its membrane. Atresting values and measured across the membrane, this voltage can benegative, and can have a small magnitude in the order of a few 10's ofmV. As shown in FIGS. 1A, 1B and 2 , the transmembrane voltage can varybased on the cell type, function and cellular activity. Thetransmembrane voltage can also vary in response to a voltage imposedfrom an external source. The membrane potential 205 can rise or fall byfew 10's of mV during normal cellular processes. The membrane potentialcan also be altered or returned to resting values by the cell throughthe coordinated action of enzymes such as Na⁺/K⁺-ATPase (“ATP”), ionpumps and voltage activated channels. It is previously known that thephysiological failure of the enzyme or ion pumps can lead to ionicimbalance and changes in osmolarity, which in extreme cases can lead tocell death. (See, e.g., FIGS. 1A-1D, 2, 3 and 4 ). The exemplary voltage(e.g., an external voltage 210) imposed upon the cell generated from anexternal source can be considered an external voltage, and can be usedto manipulate or affect the cell in some way.

FIGS. 1A-1C illustrate the change in ionic balance with respect to thechange in polarization (e.g., the polarization illustrated in FIG. 1D).As illustrated in FIG. 1A, the cell is at resting potential, which canbe established through the balance of K⁺ and Na⁺ ions in theintracellular and extracellular space. As illustrated in FIG. 1B, thecell adjusts the resting membrane potential through exchange of ionsthrough specialized gates and channels (arrows 105) to achieve adifferent membrane potential to perform cellular functions. This canalso occur in response to an externally imposed electric field. Asillustrated in FIG. 1C, the cell is shown redistributing ions in theintra and extra cellular space to return to its resting potential.

When a small external electric field (e.g., less than about 500 mV) canbe imposed on a cell, contingent on the magnitude of the field andpositive or negative nature of the field, the cell can undergohyperpolarization or depolarization. During the hyperpolarization, thetransmembrane voltage can decrease to a larger negative value, andduring depolarization the transmembrane voltage can increase to apositive value. When the external field can be removed, the cell can useATP, ion pumps and voltage activated channels to return the cell back toits resting potential value. ATP can be consumed during this process,and energy consumed in the process of returning the cell to restingvalues can amount to up to about 25-30% of a cell's total metabolicenergy consumption during this process. Additionally, it is previouslyknown that the external field can cause the activation of electricallysensitive structures in the cell, such as the plasma membrane, and thevoltage gated ion channels and pumps. These structures are also known toundergo mechanical deformation, but can rapidly return to normal shapewhen the external field can be removed. Finally, the external electricfield can cause generation and flow of inward or outward currents. (See,e.g., FIG. 2 ). The flow of currents can be dictated by the sign of theexternal fields. These bio-electric phenomena are well documented in theliterature, and can form the basis of experimental techniques (e.g.,patch clamp studies) and clinical methods (e.g., neuromuscularactivation). Such electrical stimulation of cells can be known to besafe and regularly used for therapeutic purposes.

It is previously known that deliberate application of an electric fieldin the form of discrete unipolar pulses, with a square or an exponentialshape, can result in creation of nano-sized pores in the plasmamembrane. This phenomenon is called electroporation orelectro-permeabilization, and can be contingent on the selection ofpulse parameters; the pores created in the plasma membrane can beenduring or transient. The former technique can be called irreversibleelectroporation (“IRE”), and the latter can be called reversibleelectroporation. Reversible electroporation can be used for theintroduction of molecules or genetic material into the cells. The pulseparameters for reversible electroporation can be carefully chosen tocause the cell to survive, or remain viable, following thepermeabilization process. In the case of irreversible electroporation,pulse parameters can be deliberately chosen that can result in creationof pores in cell membranes that can be permanent. Thus, the cells can beunable to recover from this process, and as a result, can undergonecrosis due to acute injury. A dramatic increase in electric impedanceof the treated tissue can be observed, or can be considered as evidenceof both reversible and irreversible forms of electroporation takingplace in the targeted cells.

The application of irreversible electroporation can be enhanced byidentifying square pulse parameters such as pulse width, appliedvoltage, number of pulses and pulse repetition time that can facilitatedelivery of IRE while minimizing the collateral rise in tissuetemperature due to the passage of electrical current. This enhancedtechnique has been termed non-thermal IRE. Non-thermal IRE can beachieved through application of pulse parameters such that a rise intransmembrane voltage of 0.7-1.0V can be achieved leading to permanentelectroporation of the tissue without cell injury due to thermalmechanisms. While the field of IRE has been reviewed, its applicationcan be enhanced by modifications that can minimize temperature relatedeffects of the pulse application. Imaging techniques can be used, suchas electrical impedance tomography that can specifically exploit thedecrease in tissue impedance following non-thermal IRE to map ablatedtissue in-vivo. Broadly, the electric field strengths of about 500-2500V/cm or about 800-1000 V/cm can be used (e.g., such that a minimumsustained threshold of about 637V/cm) is sustained to achieve IRE intissue. In addition, to achieve non-thermal IRE, the pulse width has tobe multiple times longer than that of the membrane charging time of thecell types in the target tissue, the applied voltage and its derivative,and the electric field strength can be significantly larger than whatcan be used in reversible electroporation. The number of pulses used toachieve IRE can be larger than what can be used for reversibleelectroporation, and can be such that the inter pulse spacing orduration allows for the buildup of transmembrane voltage to the desiredIRE threshold. (See, e.g., References 1-4).

Additional enhancements to IRE have been explored to exploit thetemperature dependent properties of change in the transmembranepotential to achieve IRE at thresholds that can be lower than what hasbeen reported by (see, e.g., References 1-4). This can be achieved byusing a train of two different pulses, such that the first sequence canbe used to heat the target tissue but can be insufficient to ablate thetissue by itself, and which can be followed by a second pulse sequencethat can induce IRE in the targeted region. The heating caused by thefirst pulse sequence can be used to reduce the transmembrane voltagethreshold of IRE from about 0.7-1.0V to about 0.5V. To achieve thiseffect, the first pulse sequence can be applied rapidly, with lowexternal electric field strength and the second pulse sequence can beapplied with pulse considerations such as a pulse length longer thanmembrane charging time. Inter-pulse spacing can be used to facilitatethe building of transmembrane potential and voltage thresholds that canbe sufficiently large to induce IRE. While this technique can reduce thethreshold potential requirements for achieving IRE, it can no longer beconsidered a non-thermal ablation technique. The increase intemperature, while insufficient to ablate cells, can otherwise besufficient to destroy heat sensitive structures such as bile ducts andnerves that can be in vicinity of the treatment regions. This reducessome of the benefits of non-thermal IRE. (See, e.g., References 1-7).

Another technique can use very high voltage pulsed electric fields todirectly permeabilize the nuclear membrane of cells without affectingthe plasma membrane. (See, e.g., Reference 8). This technique has beendescribed as nanoporation or supraporation. In this technique, pulses ofnanosecond width and spacing can be used in conjunction with fieldstrengths larger than about 10,000 V/cm. The pulses can have a widthmuch shorter than the membrane charging time of most cells, andtherefore, can bypass charging the plasma membrane instead of directlyaffecting membrane of intra-cellular organelles such as the nucleus andthe mitochondria. At the end of the treatment application, the cellshave been reported to undergo apoptosis due to disrupted nucleararchitecture, but the plasma or cell membrane itself may not bepermeabilized. Therefore, concomitant electrical conductivity changesseen in IRE can be absent here. Nanoporation is also believed to killcells without large temperature changes and can be considered anon-thermal ablation technique that can otherwise be benign tonon-cellular structures in the treated area.

Further enhancements to both non-thermal IRE and nanoporation can beachieved with a derivative technique called high frequency irreversibleelectroporation (“HI-FIRE”). The use of a pulsed waveform has beenresearched such that the pulses can be shorter than the membranecharging time of either the nuclear or the plasma membrane. (See, e.g.,References 9-13). A multitude of such pulses, or significantly largernumber than what can typically be used for either IRE or nanoporation,can be applied with a very short inter-pulse spacing. This arrangementcan facilitate the spatial or temporal summation of the effect of thesepulses, and effectively facilitates them to increase the transmembranepotential to achieve either nanoporation or IRE contingent on theapplied field strength. A benefit of this technique can be that it canfacilitate direction of ablation through layers such as epithelial cellsor other cells with tight gap junctions that would otherwise get chargedand ablated, therefore impeding the satisfactory ablation of anunderlying target tissue. While the pulse parameters can be differentfrom other techniques (see, e.g., References 1-7), this technique canuse a similar range of field strengths and membrane potentials (e.g.,about 0.7-1.0V) to achieve cell injury and death. (See, e.g., References9-13). The high energy electrical fields used to induce IRE, theinability to selectively target cells, the concomitant tissue edema, theimpact on electrical sensitive structures, and the effect of tissueheterogeneity on ablation outcomes can limit the application of IRE andassociated techniques in the clinical setting.

A number of energy sources and associated ablation techniques can beclinically used for the therapy of patients. Exemplary ablation methodscan be categorized on basis of the energy source used for causing injuryto the cell. Ablation that predominantly uses temperature differences tocause cell injury can be called thermal ablation techniques which caninclude radiofrequency ablation, microwave ablation, cryoablation, someforms of electrocautery and laser therapy. Another category of ablationtechniques can predominantly rely on application of strong externalelectric fields to cause pore formation in cell membranes. Thesetechniques can be broadly termed electroporation. Electroporation maynot be intended to cause permanent injury to the cell. Techniques suchas irreversible electroporation, nano or supraporation, high frequencyelectroporation and enhanced electroporation can be derivative methodswhich can be meant for inducing cell death through permanent injury.These techniques can typically be called non-thermal techniques, as theprimary cause of cell death may not be due to variations in tissuetemperature. There can be other non-thermal ablation techniques, whichinclude photodynamic therapy, argon-plasma coagulation,electrochemicaltherapy, electrochemotherapy and different forms ofradiation therapy. In addition to these, many of these ablationtechniques can be performed in combination with each other.

Thermal ablation techniques can use an applicator to provide an energysource or sink in proximity to the targeted region. Depending on thetechnique, the temperature gradient can be established throughelectromagnetic wave induced molecular friction or heating and/orcooling through adiabatic expansion of gases, joule heating processes orthe application of energy through light sources. While there can beslight variations in the exact mechanism of cell death, generally cellnecrosis can be induced through heat induced coagulation of proteins anddirect thermal injury of cell components. In the case of cryoablation,cell death can be induced through creation of intra and extra-cellularice crystals that can cause cell rupture and damage to interstitialtissue. Due to their working mechanism, there can be two fundamentalshortcomings of these thermal ablation techniques. First, the techniquecan be non-targeted, destroying all forms of tissue, extra cellularmatrix and other components that can fall within the region of alteredtemperature values. Because of this, scarring can be a common outcomefollowing ablation and also otherwise healthy tissue, vasculature andcritical structures such as nerves can also be permanently injuredduring treatment. Elevated temperatures can increase risk of perforationof lumen structures, and therefore can limit application of theseablation techniques in proximity to lumen such as the ureter, bile ductor the esophagus.

While some of these techniques have been adopted for mucosal ablationwithin lumen, their use can be limited to sub-millimeter depths. Thesetechniques may be unable to treat tissue deeper than this depth withoutsignificant risk of perforating the tissue or inducing strictures in thelong term. Some of these techniques have also been adopted for targetingnerves that can surround lumen, for example nerves surrounding the renalarteries or the bronchus. However, these ablations can be non-targetedin that they cannot selectively ablate the nerve without permanentlyinjuring or destroying tissue that lies in the path of energy delivery.Therefore in these cases, thermal ablation can damage the muscularis andadventitia of the lumen supporting the nerves. The second significantshortcoming of thermal ablation techniques can be that they can beaffected by heat sinks within the body. Perfusion and vascular flow cansignificantly affect the completeness and success with which thesetechniques can ablate cells within a target area. It may not be uncommonfor failure of these techniques in ablating tissue adjacent to largeblood vessels, which in fact can be a contra-indication for the usethese techniques. (See, e.g., FIGS. 26A and 26B).

Thus, it may be beneficial to provide an exemplary embodiment of asystem, method and computer-accessible medium for cell targeted in-vivotissue ablation, without damaging surrounding non-targeted tissues, andwhich can overcome at least some of the deficiencies described hereinabove.

SUMMARY OF EXEMPLARY EMBODIMENTS

Systems, methods and computer-accessible mediums can be provided thatcan establish particular parameters for electric pulses based on acharacteristic(s) of the tissue(s), and control an application of theelectric pulses to tissue(s) for a plurality of automatically controlledand separated time periods to ablate the tissue(s) such that anelectroporation of a majority of the tissue(s) is prevented or reduced.The electric pulses can include a waveform(s). The waveform can be basedon a (i) an applied voltage of the electric pulses, (ii) a sign of theelectric pulses, (iii) a length of exposure of the tissue(s) to theelectric pulses, (iv) a relative field strength of the electric pulses,(v) a current density of the electric pulses, or (vi) a duty cycle ofthe electric pulses. The waveform(s) can have a shape of (i) a square,(ii) a sawtooth, (iii) a triangle, (iv) a trapezoid or (v) anexponential sinusoidal pulse. The waveform can be applied as (i)monopolar, (ii) bipolar, or (iii) direct current shifted. Anapproximately stable impedance level of the tissue(s) can besubstantially maintained while the electric pulses are applied. Theimpedance level can be increased while the electric impulses areapplied.

In some exemplary embodiments of the present disclosure, a time betweenat least two of the separated time periods can be controlled based on afurther time period for the duration of which a particular cell(s) ofthe tissue(s) can substantially regain a resting value(s) before beinghyperpolarized or depolarized. The cell(s) can be (i) injured, (ii)killed, (iii) have its metabolic rate increased, (iv) have avulnerability to immune processes increased based on the electricpulses, cause heating or energy transfer through a cell membrane of thecell(s), (vi) deplete an energy or an ATP reserve of the cell(s), (vii)cause at least one of an osmotic imbalance or an ionic imbalance of theat least one cell, (viii) disrupt normal cellular processes dependent ona membrane potential of the cell(s), or (ix) deform and modifyelectrically sensitive proteins and structures on the cell membrane ofthe cell(s). A bioelectric response or at a cellular process(es) of thecell(s) can be disrupted on the electric pulses. Exemplary heating ofthe cell membrane can take place. Energy reserves of the cells can getdepleted during course of pulsation.

A specific function of the cell(s) can be impaired based on a sign of atleast one of the electric pulses. A creation of reactive oxygen speciesin intra-cellular or inter-cellular spaces of the cell(s) can be inducedto degrade a cellular structure of the cell(s). The electric pulses canbe applied using an electrode(s). A location to place the electrode(s)can be determined using (i) computed tomography, (ii) magnetic resonanceimaging or (iii) ultrasound. The electrode(s) can include a plurality ofelectrodes which can be configured to be placed substantially near andaway from the tissue(s). In some exemplary embodiments of the presentdisclosure, the electroporation of the majority of the tissue(s) can beprevented or reduced due to an effect of the electric pulses which havethe particular parameters on the tissue(s). In certain exemplaryembodiments of the present disclosure, the parameters can be based on ashape, a size, a biology or a morphology of the tissue(s). In someexemplary embodiments of the present disclosure, the tissue(s) can beablated through mediation of a cell(s) membrane potential of thetissue(s) without crossing a threshold that can induce electroporation.The mediation of the cell(s) membrane can be induced using a pluralityof charge discharge cycles. The tissue(s) can include a particular typeof tissue. The tissue(s) can include a particular type of cells.

These and other objects, features and advantages of the exemplaryembodiments of the present disclosure will become apparent upon readingthe following detailed description of the exemplary embodiments of thepresent disclosure, when taken in conjunction with the appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

Further objects, features and advantages of the present disclosure willbecome apparent from the following detailed description taken inconjunction with the accompanying Figures showing illustrativeembodiments of the present disclosure, in which:

FIGS. 1A-1C is a set of exemplary diagrams of exemplary cells withcharacteristics that can be effected by the system, method andcomputer-accessible medium for in-vivo tissue ablation according to anexemplary embodiment of the present disclosure;

FIG. 1D is an exemplary graph illustrating the resting and return toresting value state of an exemplary cell;

FIG. 2 is a set of exemplary graphs illustrating voltage and currentflow of an exemplary electric field;

FIG. 3 is an exemplary diagram of an exemplary cell being ablatedaccording to an exemplary embodiment of the present disclosure.

FIG. 4 is an exemplary diagram illustrating various exemplary stages ofthe exemplary ablation procedure according to an exemplary embodiment ofthe present disclosure;

FIG. 5 is an exemplary graph illustrating an exemplary waveformaccording to an exemplary embodiment of the present disclosure;

FIG. 6A is an exemplary map illustrating current density according to anexemplary embodiment of the present disclosure;

FIG. 6B is an exemplary map illustrating an electric field;

FIG. 7 is a set of exemplary waveform shapes according to an exemplaryembodiment of the present disclosure;

FIG. 8 is a set of exemplary graphs illustrating an exemplary waveformaccording to an exemplary embodiment of the present disclosure;

FIG. 9 is an exemplary graph illustrating an exemplary waveformaccording to an exemplary embodiment of the present disclosure;

FIG. 10 is an exemplary diagram illustrating an exemplary ablationprocedure according to an exemplary embodiment of the presentdisclosure;

FIG. 11 is an exemplary diagram illustrating a total exemplary chargeover time according to an exemplary embodiment of the presentdisclosure;

FIG. 12 is an exemplary diagram illustrating a further ablationprocedure according to an exemplary embodiment of the presentdisclosure;

FIG. 13 is an exemplary diagram of an exemplary ablation procedure on apatient according to an exemplary embodiment of the present disclosure;

FIG. 14 is a set of exemplary diagrams of exemplary electrodecross-sections according to an exemplary embodiment of the presentdisclosure;

FIG. 15 is a set of exemplary images of exemplary electrodes accordingto an exemplary embodiment of the present disclosure;

FIG. 16 is an exemplary diagram of a set of exemplary electrodesaccording to an exemplary embodiment of the present disclosure;

FIG. 17 is a set of exemplary diagrams of exemplary treatment areasaccording to an exemplary embodiment of the present disclosure;

FIG. 18 is a set of exemplary images of exemplary electrodes accordingto an exemplary embodiment of the present disclosure;

FIGS. 19A and 19B are exemplary images of further exemplary electrodesaccording to a further exemplary embodiment of the present disclosure;

FIG. 20 is a set of exemplary images of still further exemplaryelectrodes according to another exemplary embodiment of the presentdisclosure;

FIG. 21A is an exemplary drawing of an exemplary treatment areaaccording to an exemplary embodiment of the present disclosure;

FIG. 21B is an exemplary image of an exemplary treatment area accordingto an exemplary embodiment of the present disclosure;

FIG. 22 is an exemplary electrode introduced through an exemplarycatheter according to an exemplary embodiment of the present disclosure;

FIG. 23 is an exemplary block diagram of an exemplary ablationdevice/system according to an exemplary embodiment of the presentdisclosure;

FIG. 24 is an exemplary diagram of an exemplary treatment area and theexemplary ablation device/system according to an exemplary embodiment ofthe present disclosure;

FIG. 25 is a flow diagram of an exemplary procedure for ablating anexemplary treatment area according to an exemplary embodiment of thepresent disclosure;

FIG. 26A is an exemplary image of an exemplary radio frequency ablationtreatment area of the liver;

FIG. 26B is an exemplary image of an exemplary EStress treatment area ofthe liver according to an exemplary embodiment of the presentdisclosure;

FIG. 27A is an exemplary image of an exemplary lethal temperature zoneaccording to an exemplary embodiment of the present disclosure;

FIG. 27B is an exemplary image of an exemplary EStress treatment zoneaccording to an exemplary embodiment of the present disclosure;

FIG. 28 is an exemplary graph illustrating exemplary strength andexemplary exposure length of time of the exemplary electric fieldaccording to an exemplary embodiment of the present disclosure;

FIG. 29 is an exemplary graph illustrating exemplary field strength andexemplary number exposures of an exemplary electric field according toan exemplary embodiment of the present disclosure;

FIG. 30 is an exemplary graph illustrating exemplary current andexemplary time of the exemplary electric field according to an exemplaryembodiment of the present disclosure;

FIGS. 31A and 31B is an exemplary diagram illustrating exemplaryablation size and quality according to an exemplary embodiment of thepresent disclosure;

FIGS. 32A-32C are exemplary images illustrating the exemplary treatmentarea according to an exemplary embodiment of the present disclosure;

FIGS. 33A and 33B are exemplary images of the exemplary treatment areaaccording to an exemplary embodiment of the present disclosure;

FIG. 34 is a set of exemplary illustrations of the exemplary treatmentareas according to an exemplary embodiment of the present disclosure;

FIG. 35 is a set of exemplary illustrations of the exemplary treatmentareas according to an exemplary embodiment of the present disclosure;

FIGS. 36A-36C are exemplary images of exemplary treatment areasaccording to an exemplary embodiment of the present disclosure;

FIG. 37 is an exemplary image of an exemplary catheter according to anexemplary embodiment of the present disclosure;

FIG. 38 is a set of exemplary images of an exemplary placement of theexemplary catheter of FIG. 37 according to an exemplary embodiment ofthe present disclosure;

FIG. 39 is an exemplary image of an exemplary swine esophagus accordingto an exemplary embodiment of the present disclosure;

FIG. 40 is a set of exemplary images of a cross-section of stained swineesophagus treated with the exemplary EStress system/apparatus accordingto an exemplary embodiment of the present disclosure;

FIG. 41 is a set of exemplary images of normal and treated epitheliumaccording to an exemplary embodiment of the present disclosure;

FIG. 42 is an exemplary flow diagram illustrating an exemplary methodfor injuring or killing tissue and/or cells according to an exemplaryembodiment of the present disclosure; and

FIG. 43 is an illustration of an exemplary block diagram of an exemplarysystem in accordance with certain exemplary embodiments of the presentdisclosure.

Throughout the drawings, the same reference numerals and characters,unless otherwise stated, are used to denote like features, elements,components or portions of the illustrated embodiments. Moreover, whilethe present disclosure will now be described in detail with reference tothe figures, it is done so in connection with the illustrativeembodiments and is not limited by the particular embodiments illustratedin the figures and described in appended claims.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

The exemplary system, method and computer-accessible medium, accordingto an exemplary embodiment of the present disclosure, can utilizebioelectric responses and cellular processes to perform a controlledinjury, or to kill the cells. According to one exemplary embodiment, theATP exhaustion can be induced in the cell if the external electric fieldcan be applied for carefully pre-determined periods of time with timingsuch that the time between the waveform alterations can be sufficient tofacilitate the cell to regain resting values before being hyper ordepolarized again. Based on the sign of the electric field, theexemplary system, method and computer-accessible medium, according to anexemplary embodiment of the present disclosure, can be used to impairthe functioning of specific ion channels. This can lead to loss ofosmotic and ionic balance. Furthermore, the combination of ATPexhaustion and ionic imbalance can reduce the cell's ability to maintainmembrane potential, and therefore, can disrupt basic cellular processes.This repeatedly induced external electric field can also causemechanical damage to the membrane and other electro-sensitivestructures. The generation of current flow through the cell can inducecreation of reactive oxygen species (“ROS”) in the intra and intercellular spaces which can degrade cellular structures. The repeatedpassage of current through the cell can also be used to cause highlylocalized heating. This cascade of events, following exposure to anelectric field, can cumulatively or separately cause the cell to loseviability and die. (See, e.g., FIG. 3 ).

As illustrated in FIG. 3 , a cell exposed to an external voltage 210imposed upon it for a short duration of time using electrodes 305 inorder to depolarize or hyperpolarize the cell can elicit a variety ofreactions, which can include, for example i) ATP Exhaustion 310: wherethe ATP within the cell can be consumed in order to maintain osmoticbalance and to regain the cell's normal resting membrane potential; ii)Ion Flow and Imbalance 315: the polarization can also lead to ion influxinto the cell (e.g., Na²⁺ or Ca²⁺) and the loss of certain ions (e.g.,K⁺); iii) Reactive Oxygen Species (“ROS”) Damage and Infiltration 320:the flow of current can induce an electrolysis and/or an ROS formationnear the membranes; iv) Electro-Confirmational Protein/Gate/ChannelChange 325: electrically sensitive membrane proteins, including cellshaving an abundance ion channels and gates, can undergo electric fieldinduced deformation and damage; and v) Osmotic Swelling 330: thedisruption of membrane potential can also lead to loss of homeostasis,which can lead to osmotic swelling.

This process can be defined to be electrically induced stress or EStressfor short. EStress can operate as an in-vivo tissue (e.g., tissue typeor cell type) ablation technique. Through the working principle ofEStress (element 400), the waveform of the external electric field caninduce one of several biological effects on cells in vivo includingtransient cellular injury (element 405), increased metabolic rates(element 410), increased vulnerability to immune processes and can alsocause immediate and complete cell death (element 420). (See, e.g., FIG.4 ). Cells from element 410 or 425 that can be exposed, e.g., to only alimited cycle polarization can typically survive and continue tofunction normally. The EStress waveform used to cause any of theseeffects can be carefully attuned to attain a specific outcome. TheEStress waveform can be defined by several parameters including appliedvoltage, sign of the electric field, type of waveform, length of eachexposures, relative field strengths and current density, duty cycle, andintermittent or repeat exposures. (See, e.g., FIG. 5 ). While similarwaveforms can be in use for experimental techniques and otherphysiological processes, the selection of waveforms to induce EStresscan be non-trivial. Incorrect choice of even one parameter can lead toundesirable or unexpected outcomes.

Exemplary Parameters for Estress

The voltage to be applied to achieve EStress can be based on theconfiguration of electrodes used, and the biology of the target cells.The size, shape and morphology of the cells can determine the thresholdmembrane potential induced on the cell. The exemplary transmembranepotential induced on exposure to an external electric field can bedetermined using the Schwann equation, where cell shape and size can bekey determinant factors. The exemplary voltage applied upon the cellscan be high enough to cause transient rise in membrane potential but canbe lower than the electroporation threshold for the cell. While this canbe based on cell type, representative values for mammalian cells can bethe voltage that can cause increase in transmembrane potential in therange of about 100-300 mV. These values can likely be lower for largerskeletal muscle cells, and higher for smaller cells. Various exemplarystatistical methods can be used to determine values for a population ofcells where processes such as neoplasia or dysplasia can causevariations in the cell size and general morphology. For example, FIG. 6Aillustrates a current density map 600 including electrodes 605 and anexemplary boundary of the effect of the Exemplary EStress 610. FIG. 6Billustrates an Electric Field Map 615 having electrodes 605 and aboundary of electroporation 620.

The treatment voltage can be applied to the cell in a variety ofwaveforms, including square 701, sawtooth or triangle 703, trapezoidal704, exponential or sinusoidal pulses 705-709. (See, e.g., FIG. 7 ).These waveforms can be applied to the cell in monopolar, DC shifted orbipolar fashions. In case of sinusoidal or similar waveforms, thefrequency of application can be limited by root mean squared (“RMS”)voltage value, which can be larger than the cell charging time. In caseof monopolar application, the sign of the waveform can determine thepredominant current channel affected by it, for example either inward oroutward current, and also the type of ion depletion caused. (See, e.g.,Na⁺ or K⁺). The exemplary waveform can be shifted from a positive to anegative direction, or vice versa, to maximize stress induced on thecell. The bipolar waveform can offer additional advantages such asreducing stimulation of non-targeted cells, which can lead to effectssuch as minimal to no nerve or muscle activation, for example. The DCshifted waveform can provide the benefit of low level heating andgeneration of reactive oxygen species that can increase the stress onthe cell, making it more vulnerable to death or other extra-cellularprocesses. Transient localized hyperthermia can also provide the addedbenefit of reducing the voltage used to induce desired transmembranepotential. Other waveforms, such as exponential waves, can also be usedto provide a gradient for driving ROS species towards the cell, andinterfering with cell's ability to return to resting potential.

A single exposure can be defined by the exemplary waveform that caninduce increase of transmembrane potential to a desired value, and theperiod which can facilitate the cell to return to its natural restingstate. The number of exposures that the cell goes through can be theprimary determinant of the nature of injury to the cell. At optimalvoltage values and without considering other expedient factors, it canbe estimated that the cell can undergo at least 500-1000 exposures tocause permanent injury that can lead to eventual cell death. The numberof exposures to achieve cell death can be based on the biology of thecell (e.g., ion channels present on the cell membrane), and/or itsrelative age and metabolism. Given a known cell type and optimal voltagevalue, empirical data can be used to construct a statistical model, likea Peleg-Fermi formulation, to determine the number of exposures that canbe used to cause 99% or more cell death in a given population. (See,e.g., FIG. 9 ).

The exemplary waveform used to induce EStress in cells can be resolvedinto two functional components. At least one portion of the exemplarywaveform, where the voltage can be applied to elevate the transmembranevoltage, can be called the “active” portion of the exemplary waveform,and the portion of the exemplary waveform where the external voltage canbe turned off to facilitate the cell to return to resting values can becalled the “passive” portion of the exemplary waveform. (See, e.g., FIG.8 ). The active portion of the exemplary waveform can be longer than themembrane charging time of the cell, which can typically be between about1000 ns to about 100 μs in length. In case of sinusoidal or similarwaveforms, the half or quarter cycle/wavelength of the exemplarywaveform can fall within this range. The actual active portion can be asmaller portion of about 100 μs, with the remaining portion of theexemplary waveform used to induce mild hyperthermia, generate ROS, causeelectrophoretic or other effects. Conversely, the active portion can beoptimized to provide a narrow range of temperature increase in thetargeted area. The passive portion of the exemplary waveform cancorrespond to the time used by the cell to return to resting potentialvalues from the elevated values due to exposure to the active portion ofthe waveform. The length of the passive portion can be dictated by thecell biology, and electrochemical transport processes. For example, thisvalue can range from a lower range of about 10 μs for cells with rapidresponse time to about 100 ms for cells that can have slower processes.The passive portion can extend to many seconds for certain other celltypes. The passive portion may not be constant, but can increase as theexposure progresses because of cell fatigue, and accelerating stress onthe cell. The passive portion can also be monitored and altered to stopthe buildup of membrane potential which can eventually lead to undesiredelectroporation of the cell.

The waveform can be applied to a target area continuously or asfractionated treatment. The fractionation can serve two purposes. (See,e.g., FIG. 9 ). First, fractionation can facilitate for the recovery ofnon-target cells which can undergo transient EStress because ofproximity to treatment zone. Second, fractionation can facilitatepre-stressing of cells, where cells can be stressed by a first set oftreatments, facilitating completion by following sets of treatment whichcan now be delivered at a lower energy setting. This fractionation canalso be performed between sets of electrodes (e.g., spatially ortemporally). During spatial fractionation, a set of electrodes can beused to surround a target that can be embedded well within non-targettissue that can be spared. In this case, each pair or set of electrodescan deliver a portion of the total desired energy. While the energypasses through non-target tissue, it can spare it from injury as it mayonly be a fraction of what can be used to cause cell death or permanentinjury. However, in combination from all the electrodes, the targettissue can receive a larger and more complete portion of the energyleading to the desired treatment effect in this location only. The sameeffect can also be achieved by temporally fractionating the treatment,by either delivering treatment from a different pair of electrodes atdifferent time points, or by a single set of electrodes but overdifferent time points. (See, e.g., FIG. 10 ).

The current density and field strength generated in a tissueexperiencing EStress can be dependent on the applied voltage and theconfiguration of electrodes used. Globally, current density and fieldstrength can be inter-related parameters, calculated by the appliedvoltage and electrical impedance of the target tissue. Unlikeelectroporation and related techniques like irreversible electroporationand supraporation which can be driven by target field strength, EStresscan be mediated by current density imposed on the cells. The impact ofEStress on a target tissue can in turn be determined by the total chargethat can be moved through the cell, which in turn can be computed as thetemporal integration of current density in the tissue over the course oftreatment. The field strength and current density can be numericallycomputed by solving the Laplace equation of the voltage distributionover the domain of the target tissue. (See, e.g., FIG. 10 ). Theexemplary EStress can utilize the exposing of a cell to a pre-determinedsequence of exposures to electric fields. Cells in regions receivingfewer exposures that can be insufficient to induce cell death can beexpected to survive (e.g., lines 1005). As shown in FIG. 10 , EStresscan be delivered using electrode pairs, where tissue 1010 surroundingthe common current source 1010 can experience maximum exposure toelectric fields, which can lead to tissue ablation 1015. The targettissue 1020 surrounding each current sink 1025 can experience only afraction of the total exposures provided from the current source (seee.g., fractional Estress Zone 1030). Through this exemplary approach,maximum effect of EStress can be limited to a single region whilesparing tissue in the surrounding areas.

Different types of waveforms can be combined to either enhance theeffects of EStress or to achieve adjuvant effects. For example,radiofrequency waves can be combined prior to delivering the exemplaryEStress waveform to use hyperthermia to increase the sensitivity of thecell to the effects of EStress. Alternately, the same effect can beachieved by a monopolar or bipolar square waveform. Waveforms or pulsestypically used for causing electroporation can also be combined withEStress. For example, EStress can be used to alter the metabolicactivity of the cell, following which electroporation can be used tointroduce agents into the cell that can exploit the altered state of thecell. Additionally, exponential waveforms can be used to induce acombination of hyperthermia and ROS molecules that can further weakenthe cell.

Exemplary Electrodes and Other Equipment

EStress can be induced, or treatment can be delivered to tissue orcells, through the delivery of electrical energy. This exemplaryprocedure, system, device, etc., according to an exemplary embodiment ofthe present disclosure, can use at least two electrodes, for example,one positive and the other for return pathway of the electrical current.Beyond this basic condition, the actual delivery of EStress to cells ortissue can be achieved through many different exemplary electrodearrangements. For in-vivo applications, this can be broadly classifiedinto five exemplary approaches. The first exemplary approach can be apercutaneous approach where needles or long thin probes can beintroduced into a target region through skin punctures. The secondexemplary approach can be a catheter directed approach where longtubular probes with integrated electrodes can be delivered throughbodily vascular other natural lumen to the target region. The thirdexemplary approach can be an endoscopic or laparoscopic approach, wherenatural or clinically created orifices or lumen used to directspecifically designed probes for therapy to a target region. The fourthexemplary approach can be a cutaneous approach where surface electrodescan be used to target regions that can be in proximity or at asuperficial depth to the skin surface. The fifth exemplary approach canbe one where a ring of electrodes can be deployed on the skin, in anon-invasive fashion, such that they surround a deeper target fortherapy. Each of these exemplary approaches is described in furtherdetail below.

Common to all exemplary approaches, therapy can be achieved by embeddingor placing multiple electrodes in proximity of or surrounding a target,where at least one electrode can be positive and one other can provide areturn path to the current. Alternately, the electrodes can also bepaired, where each positive electrode can be paired with a correspondingreturn electrode. In this exemplary configuration, permutations of pairscan also be chosen ad-hoc to deliver EStress. The polarity of theelectrodes can be alternated as treatment can progress to reduceelectrochemical buildup. The alteration of polarity of the electrodescan also facilitate a reduced activation of electrically sensitivetissue such as nerves or muscles. Another exemplary configuration can beutilized when a multitude of current sources can be paired with a singlegrounding pad, or where the return path which can be attached on theskin surface distal to the treatment region. (See, e.g., FIGS. 11 and 13).

FIG. 11 illustrates that the total exemplary electric charge transferredthrough the target tissue can also be used to track the effectiveness ofEStress for ablation. Element 1120 is the surface of the electrode fromwhich the electric field can be deposited into the tissue. Element 1105represents the boundary where the charge can pass through cells andwhere the number of exposures can be sufficient to ablate the cells.Elements 1110 and 1115 represent isolines of constant current density.The exemplary charge density of FIG. 11 can be expected to be highest inproximity to the electrodes, and therefore, cells at that location canbe expected to undergo damage even with few exposures to the electricfield. Repeated cycles can grow the boundary of injured/uninjuredtissue, and can be used to achieve the desired volume of ablation.

As illustrated in FIG. 12 , the exemplary can be conducted using amultitude of electrode pairs 1205, where the current source and sink canbe, but do not have to be equal in number. When an exemplary therapeuticwaveform can be delivered with one pair of electrodes at a given time,the combination(s) of electrodes use for treatment delivery to untreatedtissue 1210 can be varied to achieve any shape/volume of ablation (e.g.,element 1215) in the exemplary treated tissue 1220. FIG. 13 illustratesa further exemplary configuration of the exemplary EStress. A varyingnumber of needle electrodes 1305 can act as a current source 1310 (e.g.,a catheter-directed electrode), and can be used in combination with asingle distally placed ground pad 1315 to provide a return circuit.

The distribution of current density, and the period over which theexemplary waveform can be delivered, can determine success of EStress.For a given set of electrical properties for a target tissue, thecurrent density can be determined by the distribution of electrodes inthe tissue, the cross sectional shape and geometry of the electrode, therelative position of the electrodes with respect to each other, and thedistance between each source-ground pair. The current density at anypoint in the tissue can be numerically calculated solving the Laplaceequation. (See, e.g., FIG. 14 ). The cumulative charge moved through agiven cell, a factor of induced current density and the period overwhich the waveform can be applied can be used to determine magnitude ofinjury to the cell. This can be minor, transient or permanent.

Referencing the exemplary percutaneous approach, the probes can bedesigned as thin long needles with different prismatic cross sectionswhich can be used to facilitate current density distribution in thesurrounding regions (e.g., square 1405, pentagonal 1410, circular 1415and/or star 1420). As illustrated in FIG. 15 , percutaneous probes(e.g., insulated probe 1505) can also be tined, with the tines beingused to enhance current distribution from current source 1510, create afaraday cage effect (e.g., through current return 1515) or to injectfluid media that can alter local conductivity properties to enhance theeffects of EStress. (See, e.g., FIG. 15 ). Percutaneous probes can alsobe fashioned such that they can perform a core biopsy of tissueimmediately followed by delivery of EStress treatment. (See, e.g., FIG.16 ). The exemplary probes can be arranged in pairs with mathematicalmodels used to determine treatment coverage, or they can also bearranged in a fashion such that a central source can be enclosed by aring of ground or return electrodes. This latter exemplary configurationcan facilitate the protection of electrically sensitive tissue justbeyond the target zone from unnecessary stimulation. An integratedbipolar configuration can also be created for the percutaneous probewhere both the source and return can be designed into a single probedevice. This exemplary device can also follow a tined configurationwhere the tines can act as a ground, enclosing the target region with ahomogenous dosage of EStress.

Electrodes can also be structured and/or configured for vascular ornon-vascular endoluminal access. In either case, the exemplaryelectrodes can be distributed over a catheter like device, with at leastone source and one return electrode. Alternately, the return electrodecan also be a grounding pad that can be placed distal to the target ortreatment region. (See, e.g., FIG. 17 ). The electrode on thecatheter-like device can be provided using conductive wires in formssuch as coils, baskets or tines. (See, e.g., FIG. 18 ). In theseexemplary cases, the exemplary configuration of the electrodes can befashioned to provide ablations with radial depth, or along a helical orlongitudinal cross section of the lumen. In addition to these exemplaryconfigurations, the electrode can be or can include a conductivesubstrate running the length of the catheter, or can be placed on aballoon that can be used to increase contact with the surface of thelumen. Alternately or in addition, the source and ground electrodes canbe placed on two separate catheters that can be introduced to the targetregion separately. The endoluminal devices can be configured to achievefocal, spot, or circumferential lesions by altering the electrodeplacement on the catheter.

FIG. 16 illustrates an even further electrode configuration where corebiopsy needles 1605 can be modified to serve as electrodes for ablation.Ablation with EStress can be performed after biopsy to prevent needletract seeding. In this exemplary configuration, the biopsy needles canbe used for performing an ablation (a), while sparing surroundinghealthy non-targeted tissue (b), and subsequently can be used to extractcore samples for histological assessment. FIG. 17 illustrates anexemplary delivery of EStress using catheter electrodes where thecatheter can function as either a monopolar electrode with a groundingpad 1710 (e.g., element 1705) or in a bipolar configuration (e.g.,element 1710). The return element for completing the electric circuit(element 1710) can be placed on the skin surface 1720. Lumen wall 1725can represent the target location upon which treatment is to beperformed. This can include various endoluminal locations in the body(e.g., blood vessel, bile duct, gastrointestinal duct and urinarysystem). The expected treatment boundary 1735 achieved from applicationof pulses is illustrated by element 1740.

According to one exemplary embodiment of the present disclosure,catheters or similar flexible devices can be delivered to a target siteusing either percutaneous access or access established through naturalorifices. In case of a natural orifice, the access can be establishedusing a flexible endoscope, or some similar device, which can providevisual guidance to perform the procedure. In such exemplary cases, theelectrodes that deliver EStress can be placed at the tip of longflexible devices to deliver the exemplary therapy. The tip can be in theshape of loops, button electrodes or flat surface applicators. Innerportions of large organs like the stomach, uterus and gut, and someother lumen, can potentially be targeted using this exemplary approach.Ablations can typically be directed on the surface of the organ withendoscopic visual guidance. This approach and configuration ofelectrodes can also be beneficial for use during laparoscopic orminimally invasive robotic surgery, where the probe with the electrodeat the tip can be used to clear up margins of tissue surrounding thesurgical region. Using EStress to perform this procedure provides thedistinct benefits of preserving tissue integrity in the margins, and theablation of tissue without emission of smoke or similar particulatematter. (See, e.g., FIGS. 19A and 19B). FIGS. 19A and 19B illustrateexamples of laparoscopic friendly flexible electrodes. The electrodes(e.g., element 1905) can be mounted on a flexible shaft (e.g., element1910) that can facilitate transport through a narrow working guide of aendoscopic instrument. The exemplary design can conform to the innercircumference of a lumen (see, e.g., FIG. 19A) to facilitate uniformablation. The exemplary device can also be designed to deform and placethe electrodes flatly against the target surface to direct ablation.

EStress can be applied for cutaneous or subcutaneous targets usingvarious electrode configurations. When targeting skin protrusions, thetarget can be surrounded or captured using a pair of plate electrodes,or as part of a caliper electrode. This electrode configuration canminimize seepage of therapeutic waveforms or current into surroundingnon-targeted tissue. For subcutaneous targets such as sweat glands oradipose tissue, EStress can be applied using fine needle arrays, whereindividual electrode needles can be of about 25 G or smaller in size.Needles in the array can be paired to provide localized treatmenteffects, or groups of needles can be assigned polarity to ablate alarger region. Alternately, in this exemplary configuration the needlesat the boundary and the center of the array can be of an oppositepolarity, facilitating capture of delivered energy within the targetedregion. In other exemplary configurations, arrays of button or ringelectrodes can also be employed to deliver electrical energy to thetarget region. (See, e.g., FIG. 20 ).

FIG. 20 illustrates exemplary devices that can be used for subcutaneousdelivery of the exemplary EStress. The body of the exemplary device(e.g., element 2005) can be constructed using an insulating material tosupport the electrodes (e.g., element 2010). The electrodes can consistof a number of current sinks in the periphery with a single centralcurrent source (e.g., element 2015), or the electrodes can beconstructed as plate electrodes that can be repositioned to vary thesize of the resultant ablation (e.g., element 2020).

As described above, EStress can be amenable to summation of treatmentenergy in both temporal and spatial fashions. For example, a locationdeep in the viscera, such as a location within the brain or inside somesolid organ such as the lung or the liver, can be targeted using a ringof electrodes placed on the skin surface such that they cumulativelyform a perimeter or surround the target location. Ring, plate, gel orother forms of electrodes can be used create this configuration. In thisexemplary configuration, EStress can be delivered between pairs orgroups of electrodes such that the each group of electrodes can delivera small portion of the total therapeutic dose of the energy waveform.The delivery could be sequenced such that all electrodes can be usedwithin a finite period of time. Such spatial and temporal distributionof EStress can facilitate delivery of therapeutic energy throughnon-targeted tissue such that the target can receive the full dose oftherapy, but surrounding non-targeted tissue can be completely spared ofthe effects, or can undergo only transient injury. Similar effects canalso be achieved through percutaneous needles or subcutaneous electrodearrays that can be deliberately placed in a manner similar to thatdescribed above. (See, e.g., FIGS. 10, 21A and 21B).

As illustrated in FIG. 21A, a number of current sinks 2105 (e.g., whichcan be placed subcutaneously) can be combined with a single currentsource 2110, to be placed within the target area 2115, can be combinedto achieve a targeted ablation while sparing tissue under the currentsinks. A tumor 2120 (e.g., a deep seated tumor) can be targeted using amultitude of current sinks 2105 and current sources 2110 placed on theskin surface. Ablation can be achieved by distributing fractions ofexposure between different pairs of electrodes.

For a known biological target and tissue type, the exemplarymathematical procedures can be used to precisely plan the dose ofEStress to a given target while entirely sparing, or only transientlyinjuring, surrounding non-targeted tissue.

The effects of EStress can be modulated by agents and chemicals that canbe introduced during the therapeutic procedure. These agents can alterthe local biology, or influence overall electrical properties in thetargeted region to facilitate EStress, or in other exemplary cases, toprotect non-targeted tissue. For example, wet electrodes can be createdand/or provided by introducing saline of a different tonicity tomodulate the delivery of EStress into a large lumen such as colon,esophagus or bronchus. The use of the wet electrode can protect thelumen from thermal effects that can arise due to direct tissue contactwith a metal electrode delivering large values of current. Additionally,the fluid used to create the wet electrode can also be used to induceeffects such as osmotic shock, or agents in the fluid can be used toprotect one region of the tissue while facilitating deeper penetrationof the therapeutic energy. In addition, chemical compounds, such as ionchannel blockers, or other pharmaceutical agents, can be used as part ofthe wet electrode to improve targeting of a select set of cells usingEStress. Similar wet electrodes in the form of a conductive gel can alsobe used with subcutaneous electrodes to improve targeted delivery ofEStress to targets on the skin. (See, e.g., FIG. 22 ). FIG. 22illustrates an exemplary device 2200 (e.g., using a catheter) that canbe used to deliver the exemplary EStress to a treatment zone 2205 byusing into a bodily lumen 2210 where a permeable balloon 2115 (e.g., aweeping balloon) can be used locally deliver a medium 2120 (e.g., afluid) that can modulate the EStress treatment zone.

As illustrated in FIG. 23 , exemplary circuitry used for generation ofthe exemplary EStress waveforms can include electrical equipment capableof generating sustained power high voltage waveforms (e.g., throughexemplary power supply 2305). This can be achieved through multipleprocedures, including use of a step up transformer coupled with anarbitrary waveform generator 2310 and a rectifier circuit, or acombination of a capacitor bank and fast acting switches 2315. Currentand power monitoring circuitry can be built in to the generator 2305 toensure that the waveform generated can be specific to the desiredEStress effect. A number of sensors 2320 and 2325 can be used to monitorand to modulate or control the EStress waveform being delivered usingcomputer control unit 2330 in combination with signal conditioning unit2335. This can include temperature sensors to regulate or minimizethermal effects on sensitive structures, and electrical impedance orconduction circuitry to track or control the effect of the exemplarywaveform from EStress as compared to other effects such as thermalablation or electroporation. The exemplary Estress can be controlledthrough an exemplary user interface 2340, and can further include anexemplary safety and emergency shutdown unit 2345 to shut off theexemplary Estress apparatus during an emergency. For example, theelectrical impedance measurements can be performed across electrodesdeployed in the target region using test pulses delivered prior totherapy. The test pulse can be used to perform a frequency sweep of thetarget region, and coupled with tissue specific information, can be usedto estimate the energy levels at which EStress can be applied to achieveonly desired outcomes. During treatment delivery, the same circuitry canbe used to track the generation of EStress specific effects. This canmanifest as two sets of current measurements, one during the activeportion of the waveform and the other during the passive portion of thewaveform. The current drawn from the circuit during the active portionof the waveform can be mathematically described as a decreasingexponential curve in shape, and can be analyzed accordingly. The currentin the circuit during the passive portion of the waveform can be anon-linear curve that can be based upon the polarity of the activewaveform and type of cell being treated. However, the magnitude of thepassive portion current recorded can be, for example, 2-3 orders ofmagnitude smaller than the one measured during the active portion. Ifsufficient quantity of cells in the target region can be killed, thenthe current measured during the passive portion of the treatment candecrease significantly. This can be used as an added estimate of tissueablation progress.

The exemplary equipment used to generate and deliver EStress can also becoupled with a neural and/or cardiac sensor apparatus to enhance safetyof delivery. The neural sensors can be coupled to nerves in regionsadjacent to EStress delivery to monitor undesired nerve activation, andto regulate the waveform amplitude or frequency to reduce such effects.A cardiac sensor, such as, for example, electrocardiogram (“ECG”)systems, can be coupled with the generator to facilitate EStresstreatment close to the heart, or other such sensitive tissues withoutcausing atrial fibrillation or otherwise impacting the cardiac rhythm.The delivery system can also incorporate electrical circuitry, such ascurrent measurement systems, to estimate the magnitude of chargedelivered to the target tissue, and also to follow the graph of powerdrawn to determine normal delivery of therapy. (See, e.g., FIG. 24 ).

As shown in FIG. 24 , the exemplary EStress ablation delivery (e.g.,through needle electrode 2400) can be monitored and synchronized withsensors to achieve optimal treatment outcomes. For example, a nervemonitor 2405 can be used to identify any neuoromuscular activationduring energy delivery to target tissue 2410 and a sensor gating unit2415 can adjust energy parameters to minimize such effects. ECG Sensors2420 can be used to minimize unwanted cardiac effects. The electrodedelivery of EStress can include a multitude of sensors 2425, which caninclude a current monitor (e.g., for tracking ablation progress),temperature probe (e.g., for adjusting treatment in the event ofexcessive temperature rise) and/or a physiologic function monitor. Theabove configuration and/or procedure can be controlled through aconnection to and/or via a computer/power unit 2430 (or a pluralitythereof).

In addition to the generator, the EStress delivery system can include acomputer driven graphical or control interface that can facilitate theuser to select parameters specific to target tissue biology for specificEStress mediated outcomes. The control interface can also featureswitches that can be used to commence and stop delivery of therapy, anda kill switch that can be used to safely shut down of the system in caseof adverse events. The system can feature exemplary modules that canfacilitate rapid connection and disconnection of wires and electrodesused for treatment delivery. The graphical interface can facilitatetreatment planning using one or multiple previously describedmathematical models, and facilitates the user to use computed tomography(“CT”), magnetic resonance imaging (“MM”), ultrasound or other imagingmodalities to plan relative electrode location. Additionally, thegraphical interface can provide the operator with useful feedbackregarding the progress of EStress in the target tissue.

Various imaging modalities can be used for the planning, treatmentdelivery and post-treatment confirmation following EStress in in-vivotissue. For example, CT, Ultrasound, positron emission tomography(“PET”), MM, optical imaging, endoscopy, fluorescent imaging,fluoroscopic techniques and other modalities can be used for identifyingtissue and performing calculations used for the delivery of EStress.Cells that can be lysed by effects of EStress can undergo acute necrosiswhich can immediately be identified using contrast enhanced CT imaging.Additionally, the loss viability can alter the diffusion and perfusionproperties in the treated region, facilitating the use ofmulti-parametric magnetic resonance (“MR”) imaging for confirmation oftreatment. Compared to baseline values, EStress can induce brief spikesin the metabolic activity of target cells, and this can be capturedusing exemplary PET imaging techniques. The volume of current passedthrough tissue during EStress can be readily monitored using Redox orpotentiometric chemical sensors, and can subsequently be imaged usingexemplary optical or fluorescent techniques. EStress can cause transienterythmeia and hyperemia when treating luminal targets. Such changeswhich can typically be indicative of treatment can be monitored usingsimple endoscopic techniques.

FIG. 25 illustrates a flow diagram of an exemplary ablation procedure.For example, at procedure 2505, the exemplary ablation procedure canbegin. At procedure 2510, an exemplary imaging modality can be chosen tobe used at procedure 2515 (e.g., CT 2530, ultrasound 2535, fluoroscopy2540, PET 2545, visual/optical/microscopy 2550, chemical probes/voltagesensors 2555 and/or MM 2560). At procedure 2520, a condition can bedetected (e.g., hypodense region 2565, contrast change edema 2570,contrast extravation 2375, absence of enhancement 2380,hemorrhage/hyperemia 2385, change in fluorescence 2390 and/or DWI orT1/T2 properties 2395).

Exemplary Benefits of Estress Compared with Existing Cell AblationTechniques

Disease, malignancy, quality of life or aesthetics can cause removal ordestruction of undesired tissue from the body. Two exemplary approachescan be used to achieve this, (e.g., surgical techniques and minimallyinvasive ablations). A significant difference between the two approacheslies in whether the tissue can be removed in its entirety from the body,as can be done in surgical techniques, or destroyed in-situ as can bedone during minimally invasive ablation. The minimally invasive ablationtechniques can typically be less invasive than surgical techniques, andcan provide increased quality of life benefits to the patientsundergoing treatment. As an effect, recovery times can be shorter, andthe procedure itself can be better tolerated in a broader spectrum ofpatients. Commonly, during minimally invasive ablation, some form ofenergy can be delivered through multiple means to induce physicalchanges that can in turn cause unrecoverable damage to the targettissue; killing it within the body. Physiological processes, such asimmune response or scar formation, can facilitate recovery of the tissueto a more desirable state. EStress offers all the benefits of currentlyused minimally invasive image guided ablation techniques as compared tosurgical therapy, for the removal undesirable tissue.

EStress can be or can include a biology mediated ablation technique. Forexample, EStress can ablate only the tissue or structures that have atransmembrane potential. Therefore, EStress can have no effect on extracellular matrix, adventitia or other collagenous structures that cannotsupport, nor have, a transmembrane potential. Therefore, it can bepossible to use EStress to selectively destroy cells in a region whileleaving the extra cellular matrix largely intact. This can facilitateapplication of EStress for deep ablations within a lumen or adjacent tosuch structures. This exemplary feature can also minimize scar formationwithin the tissue. Additionally, vascular supply and nerves within thetarget region can be largely preserved thereby promoting rapid recoveryfollowing ablation. Another benefit of being a biology mediatedtechnique can be the ability to target or affect one type of cells morethan the other within the ablated region. (See, e.g., FIGS. 27A and 27Bwhich illustrates lumen wall 2705, lethal temperature zone 2710 andEStress treatment zone 2715). Different cells within a region, such assmooth muscle and epithelial mucosal tissue, can present differentresponse to EStress that can be contingent on their ability to alter thetransmembrane potential, the time taken to recover to baseline values,metabolic rates and the presence or absence of certain ion channels andpumps. EStress can utilize such differences in biology of cells throughalterations in the applied waveform as defined by the parametersdescribed above. For example, it can be possible to use EStress totarget nerves surrounding the renal artery or bronchus while completelysparing the cells in the lumen itself. Such advantages are unavailablein the known thermal ablation techniques.

EStress can injure or damage one or more cells through a combination ofion and ATP depletion, ROS damage, osmotic imbalance andelectromechanical stress. These exemplary processes can rely on thealteration of the transmembrane potential of a cell. While the inductionof the transmembrane voltage can be enhanced or made easier through anincrease in local tissue temperature, it can be largely unaffected bythermal gradients such as large vessels or perfusion related cooling.Therefore, it can be possible to use EStress to injure or destroy tissueadjacent to large vessels where thermal ablation techniques can beineffective. The exemplary waveform used to induce EStress can bemodified to function equally well in both well perfused tissue such asthe kidney and liver, or poorly perfused tissue such as the lungparenchyma and adipose tissue, without affecting the overall quality orvolume of the ablation. EStress parameters are currently described foruse with physiological temperature values. As noted above, any increasein local temperature can accelerate the process, and therefore, thevoltage of the exemplary waveform can be reduced in magnitude toaccommodate these variations. Similarly, cooling can also be employed todeliberately reduce the effectiveness or slow down the speed at whichthe ablation progresses. These exemplary features can increase theindication where EStress can be applied for ablation of tissue beyondthe capabilities of known thermal ablation techniques.

Electroporation can be a known phenomenon where high voltage squarepulses can be applied to cells to create transient pores in the cellmembranes. The creation of pores can facilitate transport of materials,such as small molecules or genes, into the otherwise intact cells.Electroporation can be designed in such a way that the trauma induced tothe cell can be minimal, and it can survive following introduction ofthe foreign bodies. The theory behind electroporation can be thatrepeated application of high voltage pulses can facilitate induction oftransmembrane voltage in the range of about 350 mV or higher. This hightransmembrane voltage can cause molecular changes to the bilipid plasmamembrane with the creation of transient pores. Upon removal of theexternal electric field, the cell can repair these pores and reseal itsplasma membrane, maintaining the cell's viability. The pores can be afew nanometers in size, and have been demonstrated through computersimulations, in vitro experiments on bilipid layers and in limited butunverified cell culture studies.

Typically, the success of pore creation, and permeation of the cell, canbe demonstrated or detected in two ways. First, the creation of thepores can alter the electrical conduction properties of the cell or thetissue being exposed to the electric field. Compared to baseline values,this can be manifested by a transient but significant increase in thecurrent drawn through the tissue or cell as the pulse can be applied. Itcan also be manifested by an overall increase in current pulled throughthe tissue. The former increase in current drawn can be attributed tothe pores reducing the overall impedance to passage of current throughthe cell. The latter increase in current can be attributed to leakage ofcytoplasm into the surrounding extra cellular region, which can alterthe overall electrical conductivity properties of the tissue. Anotherexemplary method of detecting electropermeabilization can be through theuse of tissue vitality stains and fluorescent dyes that cannot permeatean intact cell membrane. For example, propidium iodide stains cannotpermeate an intact cell, but can readily permeate an electroporated celland can stain the DNA. Likewise, fluorescent chemical sensors specificto Na⁺, K⁺ or Ca²⁺ ions can be used to monitor change in transport ofions due to the electroporation process. Electroporation by itself canbe a largely benign process and may not be intended to injure or killcells. However, a number of ablation techniques derived fromelectroporation can be commonly used for injuring or destroyingundesirable tissue. (See, e.g., FIGS. 28 and 29 ).

FIGS. 28 and 29 illustrate the exemplary pulse duration-field strengthrelation when pulsed electric fields can be used to manipulate or ablatecells. Nanoporation can be characterized by very short pulse length thatcan be combined with a very high field strength. Electroporation andother related procedures can utilize s longer pulse length (e.g., about10 microseconds or longer) where cell viability can largely bedetermined by field strength. Field strength in excess of about 1000V/cm can cause irreversible cell injury while lower field strengths canfacilitate the survival of the cell. Field strength, and the number ofexposures, can also be used in combination when using pulsed electricfields. Electroporation can utilize very low energy, and therefore, theassociated temperature rise in target tissue can be limited. Cells cantypically be exposed to fewer than about 500 pulses (e.g., to maintainnon-thermal benefit), and differences in various exemplary procedurescan be determined by increasing field strength. Electroporation can usethe least field strength, while irreversible electroporation andnanoporation can employ stronger field strengths. A large number ofexposures can cause thermal effects similar to what can be reportedduring thermal irreversible electroporation. The exemplary EStress cancause some temperature change in the tissue and can be characterized byelectric fields of low field strength and exposures greater than 250pulses to achieve ablation.

The pores created during the electropermeabilization or electroporationprocess can be made to endure using a modified set of exemplarytreatment parameters. These enduring pores can cause permanent injury tothe cell through loss of homeostasis, which can lead to eventual celldeath. Here, this pore creation and cell injury can lead to cell deathas compared to electroporation where typically the cell survives andrecovers from the permeabilization process. The process of permanentpore creation during IRE can be achieved by using electric fieldstrengths which can be at least two to three times higher than what canbe used for electroporation. The higher field strength can be coupledwith larger number of square pulse repetition that facilitates creationof transmembrane voltages in the range of about 700 mV-about 1V orhigher.

The pores resultant at these very high transmembrane voltages can inducepores of a size and number that can be larger than the typicalelectroporation process, and as a consequence, the cell can be unable torepair the pores even following the removal of the external electricfield. Similar to electroporation, pores created during IRE cannot bedetected directly. However, the success of pore creation and IRE can bedetermined by measuring the electrical conductivity of tissue, andthrough the use of plasma membrane impermeable vitality stains. The porecreation process during IRE can cause permanent alteration of tissueconductivity, increasing it by a substantial value. In fact, the successof IRE can be directly correlated to the increase in magnitude ofconductivity and therefore, the corresponding rise in current driventhrough the tissue. While there are two studies reporting directevidence of pore formation through evaluation of treated tissue usingelectron microscopes, such evidence has been limited and unverifiable.In fact, it may be difficult to clearly distinguish pore formationfollowing IRE from permanent cell permeabilization because of cell deathprocesses, such as necrosis.

EStress can provide certain benefits, and can also differ in comparisonto irreversible electroporation and derivative techniques. First, forexample, the exemplary working mechanism of EStress can usepermeabilization of the target tissue. If EStress can be deliveredsuccessfully, the cells can undergo stress, and can typically die due tonecrosis, but the plasma membrane can remain intact through the durationof the treatment. Compared to other IRE derived techniques, this canresult in limited to no edema of tissue, which can be attributed toconfounding results on imaging used for follow up of the ablation. AsEStress can operate through charging and discharging of cells, powerdrawn during treatment can remain largely constant. Due to lack ofmembrane permeabilization and concomitant electrical conductivitychanges, unlike IRE and related techniques, there can be no increase incurrent drawn during EStress mediated ablation. (See, e.g., FIG. 30 ).

FIG. 30 illustrates an exemplary graph that shows differences in currentmeasured during electroporation and EStress. The exemplary current graphof EStress can be characterized by a sharp peak 3005, which can stemfrom charging of the cell membrane and can be fairly stable current fromthat point onwards. The impedance of the tissue can be stable or canincrease slightly. During irreversible or reversible electroporation,there can be a dramatic increase in intrapulse current due to fallingtissue impedance. Additionally, decreasing impedance can lead to highercurrent drawn as treatment delivery progresses. This can simplify thedesign of instruments and generators for delivery of EStress. Overall,the energy consumption for EStress can be a few times larger than IRE,but the intensity at which the energy can be consumed can be less. Thelower energy density used during delivery of EStress can reduce theinadvertent activation of neuro-muscular tissue, which can beelectrically sensitive, and can reduce the chances of sparking betweenelectrode gaps, can avoid formation of gaseous bubble formation commonto high current densities impingent on the electrodes and can minimizethe risk of current induced cardiac arrhythmia.

EStress can function through cycling a cell through multipletransmembrane charge-discharge cycles. This can be different from IREand related techniques where the repetition of pulses or exposures canbe used to build up a transmembrane charge to a critical value, reportedto be between about 0.7-1.0V, which can be the threshold used forunrecoverable disruption of the plasma membrane. During EStress, thetransmembrane voltage can exceed a value of about 0.3-0.5V, which cantypically be the lower threshold of reversible electroporation.Therefore, when compared to IRE and related techniques, a different setof treatment parameters can be used to achieve EStress of cells. First,the pulse length for EStress can be a few times longer than the chargingtime of the cell. Compared to IRE derived techniques, the pulse lengthcan be shorter than that of the transmembrane charging time of othertechniques. (See, e.g., References 3 and 4). The EStress pulse lengthcan be magnitudes shorter than the length of other techniques forachieving non-thermal IRE. (See, e.g., Reference 1). Second, theinter-pulse spacing reported for all electroporation related techniquescan be significantly shorter than that of the discharge time for a givencell. For achieving optimal EStress effects, the passive portion or theinter-pulse timing can be at least as long as the discharge time for agiven cell. Finally, the electric field strength used to induce EStresseffects can be significantly smaller than typical values reported fornon-thermal IRE or temperature enhanced IRE (e.g., about 500-800 V/cm),supraporation (e.g., about 1 kV or higher) or high frequencyelectroporation (e.g., about 500-2500 V/cm for IRE and about 1 kV orhigher for supraporation). The threshold for inducing EStress can havean upper bound where the early effects of electroporation beginmanifesting (e.g., about 350-500 V/cm).

IRE can be an electric field strength driven threshold phenomenon, whileEStress can be based on the total charge driven through a given tissue.(See, e.g., FIG. 31 ). This can be a fundamental difference betweenthese two techniques with radically different mechanisms of action, andtechniques used to plan, deliver or monitor the treatment. High fieldstrengths can be used for achieving IRE in tissue, where the strongelectric fields can facilitate the charging of cell membranes, which canbe analogous to capacitors in an electric circuit. IRE, or evenelectroporation, may not occur unless certain electric field strengthvalues can be achieved; these values have been reported to be in excessof about 500 V/cm. (See, e.g., References 1, 2 and 4). While an electricfield can be used to induce a transmembrane charge for performingEStress, the stress on the cell can be induced through repeatedcharge-discharge cycles. Therefore, effects of EStress can be predicatedon the total charge moved through a given cell, which in turn can bedirectly related to the temporal integration of current density inducedin a tissue. Therefore, it can be possible to achieve effects of EStressat external field strengths typically too low to induce anyelectroporation.

FIGS. 31A and 31B illustrate the contrast evolution of a tissue injuryover the course of two treatments. The exemplary EStress is illustratedin FIG. 31A and electroporation based modalities are illustrated in FIG.31B. The treatment can be centered around a single electrode 3105 and adistal ground pad. Boundary 3110 demonstrates the maximum extent of cellinjury at the end of treatment delivery. Shaded region 3115 representslocations of complete cell death (e.g., ablation). The time evolution oftreatment occurs from the top to the bottom of FIG. 31A. During theexemplary EStress, a repeated exposure can cause radially increasingvolume of cell death with respect to the electrode center. During theelectroporation-based therapies, the extent of cell death can beestablished even with the first pulses, the completeness of cell deathcan be achieved with an increased number of pulses.

EStress can be and/or include a biologically modulated ablationtechnique. There can be biological and morphological differences ofcells in a region that can be used to target one type of cell whilesparing others. Conversely, IRE can be a treatment parameter modulatedtechnique where, if satisfactory thresholds are achieved, most or allcells within a target region can be destroyed. As an added benefit,treatment parameters of EStress can be adjusted to achieve varyingdegree of cell injury or stress levels. Therefore, using EStress, themolecular transport can be transiently increased, the, metabolicactivity can be increased, moderate injury can be caused or cells can bedamaged beyond recovery. Such controlled injury of cells cannot beachieved using IRE. IRE can either achieve complete and irreversibledamage to cells, or cause reversible electroporation where the cellrecovers. Additionally, effects of EStress can be enhanced or blockedcompletely through use of simple pharmacological agents such as ionchannel blockers or inhibitors, or ion channel promoters, to selectivelytarget certain cells while inhibiting effects on other cells withintreatment zone. In addition, commonly used non-pharmacological agentssuch as dextrose, physiological saline etc., can be used to alterloco-regional tissue conductivity properties and ion availability can beused to alter the progress of EStress in a heterogeneous tissue target.

EStress can provide safety benefits when compared with IRE andderivative techniques. EStress can be delivered at field strengths andvoltage values that are magnitudes less than what can be commonly usedto achieve IRE. This brings increased safety when applying EStressadjacent to electrically sensitive tissue such as the heart, muscle andnerves. As a non-targeted treatment technique, IRE can ablate muscularislayers of lumen structures. This can typically result in strictureformation and affects function of the lumen. EStress can be programmedto target mucosal layers while largely sparing the muscularis layers ofa lumen, thus being a better candidate for performing mucosalresections.

There exist few other non-thermal electrically mediated ablationtechniques. Electrochemotherapy (“ECT”) and electrogenetherapy (“EGT”)are examples of electroporation mediated therapies that do not involveIRE, but work through electroporation to introduce chemicals or genesinto target cells for purposes that can include ablation. In addition topreviously described benefits, EStress does not rely on additionalpharmacological agents or genes for performing ablations. Any suchagents can be merely adjuncts to the effects achieved by electrochemicaltherapy derived method for performing ablations are known. (See, e.g.,Reference 5). They can be achieved by inducing localized electrolysisthrough delivery of DC current into target tissue, and the use ofelectroporation as an adjunct to enhance the cytotoxic effect of theradicals generated during the electrolysis process. Compared to thistechnique, EStress can cause little to no electrochemical change in thetreated tissue. Electrochemical denaturation of tissue can causeunwanted effects including destruction of protein structures, which canbe the cause of venous embolism. Additionally, the application of steadyDC currents cannot be performed close to cardiac tissue. As EStress doesnot induce tissue electrolysis, it is beneficial over previously knownprocedures (see, e.g., References 5, 6, 7) where sinusoidal waves atdifferent frequencies can be applied to limit tumor growth. Thesetechniques are not meant to ablate tissue, but are meant to arrest thecontinued growth of cells by interfering with the cell division process.

Three examples are presented where EStress can be evaluated, in-vivo,using different application modalities. In the first exemplary case,EStress delivery can be planned in healthy swine liver using pair ofneedle electrodes. Needle spacing of about 1.5 cm and electrodedimension of about 1.5 cm can be assumed for delivery of treatment.External electric fields of about 500, 700 and 1000 V/cm. For the givenneedle electrode geometry and configuration, these field strengths cantypically be considered insufficient for causing IRE. Current drawnduring delivery of EStress can be monitored, and no change in themagnitude of current drawn can be observed, which can indicate a lack ofelectroporation or related effects. The cells in the treatment regioncan be charged and discharged about 450 times (e.g., for about 500 V/cm)or about 900 times (e.g., about 700 and 1000 V/cm), with treatmentfractionated into groups of about 90 charge-discharge cycles. Theanticipated treatment zones can be computed using numerical simulationby solving the Laplace distribution of electric potential and thePeleg-Fermi formulation.

Entire treatments were concluded between about 8-16 minutes based on anumber of cycles used. The animals were sacrificed within about 4 hoursfollowing delivery of EStress to their liver, and the ablated regionscan be extracted for histopathology analysis. Unaffected blood vesselswere found well within the region of ablation, and did affectprogression of treatment. Gall bladder close to the treatment zone wasfound to be ablated but be structurally intact without perforation.These can be interpreted as evidence that EStress therapy delivery cancause temperature rises insufficient for protein denaturation. Ablatedregions presented as areas where cells underwent a mixture ofcoagulative necrosis and apoptosis. Histological analysis andmeasurements can provide evidence that lesion size can be contingent oninduced current densities and number of charge-discharge cycles. Theablation can grow with increasing charge-discharge cycles providingevidence for EStress being a function of threshold charge moved throughgiven tissue type. (See, e.g., FIGS. 32A-32C).

FIG. 32A illustrates a photograph of a gross liver tissue specimentreated with EStress using needle electrodes. The treated regions 3205appear darker when compared to surrounding normal untreated tissue 3210.FIG. 32B illustrates a low magnification Hematoxylin & Eosin (“H&E”)stained tissue slice where the needle tract 3215 can be seen in thecorner of the image. The tissue appears hyperemic and darker whencompared to surrounding untreated tissue. A blood vessel 3220 can beseen in the vicinity of the ablation zone and has not affectedprogression of treatment. FIG. 32C illustrates the contrast enhanced CTscans corresponding to the location of treatment from where the grosstissue specimens were recovered.

In a second example of application EStress, this exemplary ablationtechnique can be used for the focal mucosal resection of the swinerectal wall. A specially constructed endo-rectal probe in monopolarconfiguration in conjunction with a grounding pad was used forperforming EStress directed mucosal ablation using two charge-dischargecycle settings in six animals. The endo-rectal electrode facilitatedablation of about 90° arc of the rectum, with about a 2 cm×1 cm crosssection. EStress treatment was delivered at a voltage of about 500V forabout 450 or 900 charge-discharge cycles. Current drawn during EStresswas monitored to confirm explicit charge-discharge patterns. Compared toa control group of IRE directed ablations performed using the sameelectrode, EStress samples demonstrated less tissue edema, hemorrhageand were limited to the mucosal tissue. In addition, during IRE,increases in current drawn by the tissue can be observed, a classicalindication of electroporation of tissue. Such increases can be absentduring delivery of EStress. The animals were sacrificed within about 4hours following delivery of EStress to their rectum, and the ablatedregions was extracted for histopathology analysis. The EStress ablationperformed at the lower cycle setting indicated evidence of patchy andincomplete ablation, with some regions of viable tissue interleaved withablated tissue. The mucosa was largely ablated with little to nopenetration to the muscle layers. In the higher cycle setting themucosal layer was found to be uniformly and completely ablated withminor penetration of ablation into the muscularis layers. However,compared with the IRE ablations performed with similar setting, thelesions was found to be more superficial and controlled with minimaledema. (See, e.g., 34A and 34B).

An exemplary comparison of an irreversible electroporation isillustrated in FIG. 34A, and the exemplary EStress is illustrated inFIG. 34B, for a treated swine rectum. The IRE treated rectum can becharacterized by tissue edema (e.g., from the release of cytosol fromelectroporation), with hemorrhage and collagen separation. Changes inEStress ablated rectum can be milder, with limited tissue edema, and theinjury can largely be limited to the mucosa.

In the third exemplary demonstration of EStress, catheter directedablation of the bronchial mucosa was attempted in a healthy swine model.Two different exemplary approaches were used for the delivery ofEStress. In the first exemplary approach the lung was isolated andfilled with normal saline, following which EStress was delivered using acatheter with a coil electrode at its tip to achieve circumferentialablation of the bronchial mucosa. In the second approach, a catheter wasmade with a sponge like material at its tip. (See, e.g., FIGS. 34 and 35). FIG. 34 illustrates an exemplary procedure where a balloon catheter3405 can be used to occlude a bronchi to fill a segment of the lung witha conductive fluid. The exemplary EStress ablation can then be performedin a target segment. FIG. 35 illustrates an exemplary procedure wherethe catheter tip is wetted with a conductive fluid 3505 to perform moretargeted ablations.

The catheter was introduced into the bronchus, and saline was passedthrough the distal end to complete the electrical pathway. Current wasdelivered through this “wet electrode” and a grounding pad to performablation of the bronchial mucosa. Previously described treatmentparameters were used in both catheter directed treatment experiments,and ablation was achieved successfully. For both cases treatment wascompleted successfully without incident and desired mucosal ablation canbe achieved. (See, e.g., FIGS. 36A-36C). FIGS. 36A and 36B illustratetreated (arrows 3605) and untreated (arrows 3610) segments of swinebronchus. FIG. 36C illustrates low magnification images of H&E stainedbronchial tissue. Treated tissue can be characterized by loss ofepithelium, and necrosis of glands.

FIG. 37 illustrates an exemplary image of an exemplary catheter 3700.Such exemplary catheter 3700 can be used to ablate an exemplary tissue(e.g., esophageal mucosa in a normal swine model). FIG. 38 shows a setof exemplary images of an exemplary placement of the exemplary catheter3700 of FIG. 37 . The exemplary images illustrate the placement ofcatheter electrode 3800 at various exemplary locations within theesophagus (e.g., within the peri-cardiac region). The exemplary catheter3700 can be used to ablate tissue without significant cardiac adverseevents. Post-treatment the patency of the lumen can be demonstrated bythe absence of extravasation of the injected contrast.

FIG. 39 illustrates an exemplary image of an exemplary swine esophagus.A gross examination of the swine esophagus illustrates circumferentialregions of discoloration and hyperemia consistent with EStress mediatedablation. There can be a small amount, or zero, tissue edema, which cannormally be observed during electroporation. Element 3905 provides thelocations of exemplary lumen that can receive treatment, Element 3910provides a location of sham balloon placement without delivery of theexemplary EStress.

FIG. 40 shows a set of exemplary images of an exemplary cross-section ofphotomicrograph of an H&E stained swine esophagus treated with theexemplary EStress. Various layers of the swine esophagus can be seenincluding: Mucosa 4010, Depth of Treatment Effect 4015, Submucosa 4020and Smooth Muscle Layer 4025. Elements 4005 indicate the extent ofpenetration of the ablation. The exemplary EStress parameters werechosen to target the epithelial type cells in the mucosa while theunderlying smooth muscle cells in the muscularis were spared.

FIG. 41 shows a set of exemplary images of normal and treatedepithelium. High magnification image of the mucosa is illustrated, whichshows morphological differences between viable and necrotic epithelialcells in the mucosa.

FIG. 42 illustrates an exemplary flow diagram illustrating an exemplarymethod 4200 for injuring or killing cells and/or tissue. For example, atprocedure 4205, parameters for electric pulses can be established ordetermined based on one or more characteristics on the tissue to beinjured or killed. At procedure 4210, the location of the placement ofthe electrode (e.g., at or near the tissue) can be determined, and theelectrode can be placed at or near the tissue in procedure 4215. Inprocedure 4220, electrical pulses can be generated for which anapplication of the electrical pulses can be controlled at procedure4225. At procedure 4230, the cells and/or tissue can be injured orkilled.

In a further exemplary embodiment, the exemplary catheter of theexemplary EStress device/apparatus can include at least one fixedelectrode (a first electrode), and at least one electrode (a secondelectrode) that can move relative to the fixed electrode. Thisfacilitates the ability to control for the length of lesions withouthaving to perform multiple repositions between ablations. The secondelectrode can be made of material that can be impedance matched to thetarget tissue being ablated, and can be surrounded by a conductive fluidthat can also be impedance matched to achieve specific ablation effects.The conductive fluid can serve as a conductor for electricalconnectivity, but can also be used as a heat sink to reduce or enhancethe thermal effects of ablation, and can serve as a reservoir fordelivery of chemicals and therapeutic agents to the target regions. Theexemplary device can have both temperature and electrical sensors tomonitor the course of the ablation. Ablations that can be performedusing this exemplary device can include, but is not limited, toradiofrequency ablation, irreversible electroporation, electroporation,electrochemical therapy, electrochemotherapy, electrogenetherapy,induced endocytosis, high frequency electroporation, nanoporation andfinally, EStress. The exemplary device can also perform transmuralablation penetrating into surrounding tissue without causing perforationor heat induced stricture of the lumen.

FIG. 43 shows a block diagram of an exemplary embodiment of a systemaccording to the present disclosure. For example, exemplary proceduresin accordance with the present disclosure described herein can beperformed by a processing arrangement and/or a computing arrangement4302. Such processing/computing arrangement 4302 can be, for example,entirely or a part of, or include, but not limited to, acomputer/processor 4304 that can include, e.g., one or moremicroprocessors, and use instructions stored on a computer-accessiblemedium (e.g., RAM, ROM, hard drive, or other storage device).

As shown in FIG. 43 , e.g., a computer-accessible medium 4306 (e.g., asdescribed herein above, a storage device such as a hard disk, floppydisk, memory stick, CD-ROM, RAM, ROM, etc., or a collection thereof) canbe provided (e.g., in communication with the processing arrangement4302). The computer-accessible medium 4306 can contain executableinstructions 4308 thereon. In addition or alternatively, a storagearrangement 4310 can be provided separately from the computer-accessiblemedium 4306, which can provide the instructions to the processingarrangement 4302 so as to configure the processing arrangement toexecute certain exemplary procedures, processes and methods, asdescribed herein above, for example.

Further, the exemplary processing arrangement 4302 can be provided withor include an input/output arrangement 4314, which can include, forexample, a wired network, a wireless network, the internet, an intranet,a data collection probe, a sensor, etc. As shown in FIG. 43 , theexemplary processing arrangement 4302 can be in communication with anexemplary display arrangement 4312, which, according to certainexemplary embodiments of the present disclosure, can be a touch-screenconfigured for inputting information to the processing arrangement inaddition to outputting information from the processing arrangement, forexample. Further, the exemplary display 4312 and/or a storagearrangement 4310 can be used to display and/or store data in auser-accessible format and/or user-readable format.

The foregoing merely illustrates the principles of the disclosure.Various modifications and alterations to the described embodiments willbe apparent to those skilled in the art in view of the teachings herein.It will thus be appreciated that those skilled in the art will be ableto devise numerous systems, arrangements, and procedures which, althoughnot explicitly shown or described herein, embody the principles of thedisclosure and can be thus within the spirit and scope of thedisclosure. Various different exemplary embodiments can be used togetherwith one another, as well as interchangeably therewith, as should beunderstood by those having ordinary skill in the art. In addition,certain terms used in the present disclosure, including thespecification, drawings and claims thereof, can be used synonymously incertain instances, including, but not limited to, e.g., data andinformation. It should be understood that, while these words, and/orother words that can be synonymous to one another, can be usedsynonymously herein, that there can be instances when such words can beintended to not be used synonymously. Further, to the extent that theprior art knowledge has not been explicitly incorporated by referenceherein above, it is explicitly incorporated herein in its entirety. Allpublications referenced are incorporated herein by reference in theirentireties.

EXEMPLARY REFERENCES

The following references are hereby incorporated by reference in theirentirety.

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What is claimed is:
 1. A non-transitory computer-accessible mediumhaving stored thereon computer-executable instructions for ablating atleast one electrically-sensitive tissue, wherein, when a computerhardware arrangement executes the instructions, the computer hardwarearrangement is configured to perform procedures comprising: establishingparticular parameters for electric pulses based on at least onecharacteristic of the at least one electrically-sensitive tissue;controlling an application of the electric pulses to all of the at leastone electrically-sensitive tissue for a plurality of automaticallycontrolled and separated time periods to ablate less than all of the atleast one electrically-sensitive tissue such that a substantialelectroporation of a majority of the at least one electrically-sensitivetissue is at least one of prevented or reduced; and controlling animpedance level of the at least one electrically-sensitive tissue whilethe electric pulses are applied.
 2. The computer-accessible medium ofclaim 1, wherein the at least one electrically-sensitive tissue is atleast one of (i) cardiac tissue or (ii) at least one nerve.
 3. Thecomputer-accessible medium of claim 1, wherein the computer hardwarearrangement is further configured to control the application of theelectric pulses to at least one of (i) hyperpolarize or (ii) depolarizeat least one particular cell of the at least one electrically-sensitivetissue.
 4. The computer-accessible medium of claim 1, wherein thecomputer hardware arrangement is further configured to: apply theelectric pulses using at least one electrode; and modify at least onewaveform of the electric pulses based on a polarity of the at least oneelectrode.
 5. A method for ablating at least one electrically-sensitivetissue, comprising: using a computer hardware arrangement, establishingparticular parameters for electric pulses based on at least onecharacteristic of the at least one electrically-sensitive tissue;controlling an application of the electric pulses to all of the at leastone electrically-sensitive tissue for a plurality of automaticallycontrolled and separated time periods to ablate less than all of the atleast one electrically-sensitive tissue such that an electroporation ofa majority of the at least one electrically-sensitive tissue is at leastone of prevented or reduced; and controlling an impedance level of theat least one electrically-sensitive tissue while the electric pulses areapplied.
 6. The method of claim 5, wherein the electric pulses includeat least one waveform.
 7. The method of claim 6, wherein the at leastone waveform is based on at least one of (i) an applied voltage of theelectric pulses, (ii) a sign of the electric pulses, (iii) a length ofexposure of the at least one electrically-sensitive tissue to theelectric pulses, (iv) a relative field strength of the electric pulses,(v) a current density of the electric pulses, or (vi) a duty cycle ofthe electric pulses.
 8. The method of claim 6, wherein the at least onewaveform has a shape of at least one of (i) a square, (ii) a sawtooth,(iii) a triangle, (iv) a trapezoid, or (v) an exponential sinusoidalpulse.
 9. The method of claim 6, further comprising applying at leastone waveform as at least one of (i) monopolar, (ii) bipolar, or (iii)direct current shifted.
 10. The method of claim 5, wherein the at leastone electrically-sensitive tissue is at least one of (i) cardiac tissue,or (ii) at least one nerve.
 11. The method of claim 5, furthercomprising controlling the application of the electric pulses to atleast one of (i) hyperpolarize or (ii) depolarize at least oneparticular cell of the at least one electrically-sensitive tissue. 12.The method of claim 5, further comprising at least one of (i) injuringat least one cell of the at least one electrically-sensitive tissue,(ii) killing the at least one cell, (iii) increasing a metabolic rate ofthe at least one cell, (iv) increasing a vulnerability to immuneprocesses of the at least one cell based on exposure to the electricpulses, (v) causing heating or energy transfer through a cell membraneof the at least one cell, (vi) depleting at least one of an energy or atleast one ATP reserve of the at least one cell, (vii) causing at leastone of an osmotic imbalance or an ionic imbalance of the at least onecell, (viii) disrupting normal cellular processes dependent on amembrane potential of the at least one cell, (ix) deforming andmodifying electrically-sensitive proteins and structures on the cellmembrane of the at least one cell, (x) repeatedly altering apolarization of the at least one cell, or (xi) interfering with atransmembrane potential of the at least one cell.
 13. The method ofclaim 5, further comprising disrupting at least one of at least onebioelectric response or at least one cellular process of at least onecell of the at least one electrically-sensitive tissue based on theelectric pulses.
 14. The method of claim 5, further comprising: applyingthe electric pulses using at least one electrode; and modifying at leastone waveform of the electric pulses based on a polarity of the at leastone electrode.
 15. The method of claim 14, further comprisingdetermining a location where to place the at least one electrode usingat least one of (i) computed tomography, (ii) magnetic resonanceimaging, (iii) ultrasound, (iv) positron emission tomography, (v)fluorescence imaging, or (vi) direct visual imaging using a camera. 16.The method of claim 14, wherein the at least one electrode includes aplurality of electrodes which are configured to be placed near and awayfrom the at least one electrically-sensitive tissue.
 17. The method ofclaim 5, wherein the electroporation of the majority of the at least oneelectrically-sensitive tissue is at least one of prevented or reduceddue to an effect of the electric pulses which have the particularparameters on the at least one electrically-sensitive tissue.
 18. Themethod of claim 5, wherein the particular parameters are based on atleast one of a shape, a size, a biology or a morphology of the at leastone electrically-sensitive tissue.
 19. The method of claim 5, furthercomprising ablating the at least one electrically-sensitive tissuethrough mediation of at least one cell membrane potential of the atleast one electrically-sensitive tissue without crossing a thresholdthat induces electroporation.
 20. The method of claim 19, furthercomprising inducing the mediation of the at least one cell membranepotential using a plurality of charge discharge cycles.
 21. The methodof claim 5, wherein the at least one electrically-sensitive tissueincludes at least one particular type of electrically-sensitive tissue.22. The method of claim 5, wherein the at least oneelectrically-sensitive tissue includes at least one particular type ofcells.
 23. A method for ablating at least one electrically-sensitivetissue, comprising: using a computer hardware arrangement, establishingparticular parameters for electric pulses based on at least onecharacteristic of the at least one electrically-sensitive tissue;controlling an application of the electric pulses to all of the at leastone electrically-sensitive tissue for a plurality of automaticallycontrolled and separated time periods to ablate less than all of the atleast one electrically-sensitive tissue such that an electroporation ofa majority of the at least one electrically-sensitive tissue is at leastone of prevented or reduced; and impairing a specific function of atleast one cell of the at least one electrically-sensitive tissue basedon a sign of at least one of the electric pulses.
 24. A method forablating at least one electrically-sensitive tissue, comprising: using acomputer hardware arrangement, establishing particular parameters forelectric pulses based on at least one characteristic of the at least oneelectrically-sensitive tissue; controlling an application of theelectric pulses to all of the at least one electrically-sensitive tissuefor a plurality of automatically controlled and separated time periodsto ablate less than all of the at least one electrically-sensitivetissue such that an electroporation of a majority of the at least oneelectrically-sensitive tissue is at least one of prevented or reduced;and inducing a creation of reactive oxygen species in at least one ofintra-cellular or inter-cellular spaces of at least one cell of the atleast one electrically-sensitive tissue to degrade a cellular structureof the at least one cell.
 25. A system for ablating at least oneelectrically-sensitive tissue, comprising: a computer hardwarearrangement configured to: establish particular parameters for electricpulses based on at least one characteristic of the at least oneelectrically-sensitive tissue; control an application of the electricpulses to the at least one electrically-sensitive tissue for a pluralityof automatically controlled and separated time periods to ablate the atleast one electrically-sensitive tissue such that an electroporation ofa majority of the at least one electrically-sensitive tissue is at leastone of prevented or reduced; and control an impedance level of the atleast one electrically-sensitive tissue while the electric pulses areapplied.
 26. The system of claim 25, wherein the at least oneelectrically-sensitive tissue is at least one of (i) cardiac tissue or(ii) at least one nerve.
 27. The system of claim 25, wherein thecomputer hardware arrangement is further configured to control theapplication of the electric pulses to at least one of (i) hyperpolarizeor (ii) depolarize at least one particular cell of the at least oneelectrically-sensitive tissue.
 28. The system of claim 25, wherein thecomputer hardware arrangement is further configured to: apply theelectric pulses using at least one electrode; and modify at least onewaveform of the electric pulses based on a polarity of the at least oneelectrode.
 29. A non-transitory computer-accessible medium having storedthereon computer-executable instructions for ablating at least oneelectrically-sensitive tissue, wherein, when a computer hardwarearrangement executes the instructions, the computer hardware arrangementis configured to perform procedures comprising: establishing particularparameters for electric pulses based on at least one characteristic ofthe at least one electrically-sensitive tissue; controlling anapplication of the electric pulses to all of the at least oneelectrically-sensitive tissue for a plurality of automaticallycontrolled and separated time periods to ablate less than all of the atleast one electrically-sensitive tissue such that a substantialelectroporation of a majority of the at least one electrically-sensitivetissue is at least one of prevented or reduced; and performing at leastone of: impairing a specific function of at least one cell of the atleast one electrically-sensitive tissue based on a sign of at least oneof the electric pulses, or inducing a creation of reactive oxygenspecies in at least one of intra-cellular or inter-cellular spaces ofthe at least one cell of the at least one electrically-sensitive tissueto degrade a cellular structure of the at least one cell.
 30. A systemfor ablating at least one electrically-sensitive tissue, comprising: acomputer hardware arrangement configured to: establish particularparameters for electric pulses based on at least one characteristic ofthe at least one electrically-sensitive tissue; control an applicationof the electric pulses to the at least one electrically-sensitive tissuefor a plurality of automatically controlled and separated time periodsto ablate the at least one electrically-sensitive tissue such that anelectroporation of a majority of the at least one electrically-sensitivetissue is at least one of prevented or reduced; and perform at least oneof: impair a specific function of at least one cell of the at least oneelectrically-sensitive tissue based on a sign of at least one of theelectric pulses, or induce a creation of reactive oxygen species in atleast one of intra-cellular or inter-cellular spaces of the at least onecell of the at least one electrically-sensitive tissue to degrade acellular structure of the at least one cell.